The present invention is generally related to compounds useful as adenosine receptor ligand and more particularly to compounds showing activity as modulators of the andenosine receptor system.
Several compounds related to general formula I have been reported.
The present invention relates to the use of compounds of the general formula 
wherein
A is a bond, xe2x80x94Sxe2x80x94, xe2x80x94N(R)xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94Oxe2x80x94;
X/Y are independently from each other xe2x80x94Nxe2x95x90 or xe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90 or xe2x95x90CHxe2x80x94, xe2x80x94C(cyano)xe2x95x90 or xe2x95x90C(cyano)xe2x80x94, or xe2x80x94C[C(S)xe2x80x94NH2]xe2x95x90 or xe2x95x90xe2x80x94C[C(S)xe2x80x94NH2]xe2x80x94, wherein at least one of X or Y is nitrogen;
R1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, cyano, cycloalkyl or the following groups
xe2x80x94(CH2)nxe2x80x94C(O)O-lower alkyl,
xe2x80x94(CH2)nxe2x80x94C(O)O-lower alkyl-phenyl,
xe2x80x94(CH2)nxe2x80x94NHxe2x80x94C(O)O-lower alkyl-phenyl,
xe2x80x94(CH2)nxe2x80x94O-lower alkyl,
xe2x80x94(CH2)nxe2x80x94O-phenyl,
xe2x80x94(CH2)nxe2x80x94NH-phenyl,
xe2x80x94(CH2)n-phenyl, optionally substituted by 1 or 2 substituents, selected from hydroxy, lower alkoxy, lower alkyl, CF3-lower alkenyl, halogen, CF3, OCF3, amino,
xe2x80x94(CH2)nxe2x80x94N-di-lower alkyl, xe2x80x94C(O)NH-lower alkyl or xe2x80x94S(O)2-lower alkyl, or is xe2x80x94(CH2)n-morpholinyl,
xe2x80x94(CH2)n-amino, optionally substituted by lower alkyl or benzyl,
xe2x80x94(CH2)n-piperidin-1-yl or xe2x80x94(CH2)n-piperidin-3-yl, which are optionally substituted by lower alkyl,
xe2x80x94(CH2)n-pyridin-2-yl, xe2x80x94(CH2)n-pyridin-3-yl or xe2x80x94(CH2)n-pyridin-4-yl, which are optionally substituted by 1 or 2 substituents, selected from lower alkyl, hydroxy, nitro, cyano, halogen, CF3 or xe2x80x94OC(O)N(R)2, or is
xe2x80x94(CH2)nxe2x80x94NH-pyridin-2-yl, optionally substituted by lower alkyl or halogen,
xe2x80x94(CH2)n-piperazin-4-yl, optionally substituted by lower alkyl, phenyl or carbonyl-phenyl,
xe2x80x94(CH2)n-phenylxe2x80x94OC(O)-phenyl, optionally substituted by halogen, or the group 
xe2x80x94(CH2)nxe2x80x94S-phenyl or xe2x80x94(CH2)nxe2x80x94S(O)2-phenyl,
xe2x80x94(CH2)nxe2x80x94S-lower alkyl,
xe2x80x94(CH2)n(CHxe2x95x90CH)m-phenyl,
xe2x80x94(CH2)n(CHxe2x89xa1CH)m-phenyl,
xe2x80x94(CH2)nxe2x80x94NH-cycloalkyl,
xe2x80x94(CH2)nxe2x80x94NH-phenyl, optionally substituted by amino or nitro,
xe2x80x94(CH2)n-tetrahydro-pyran-4-yl,
xe2x80x94(CH2)n-quinolin-2-yl,
xe2x80x94(CH2)n-naphthyl or xe2x80x94(CH2)nxe2x80x94NH-naphthyl,
xe2x80x94(CH2)n-3,4-dihydro-1H-isoquinolin-2-yl,
xe2x80x94(CH2)nxe2x80x94benzo[1,3]dioxolyl,
xe2x80x94(CH2)nxe2x80x94NHxe2x80x94S(O)2-phenyl, optionally substituted by halogen,
xe2x80x94(CH2)n-1,2,3,4-tetrahydro-quinolin-2-yl, optionally substituted by lower alkyl or
xe2x80x94(CH2)n-furanyl;
R2 is hydrogen, halogen, cyano, nitro, lower alkyl, lower alkenyl, xe2x80x94C(O)-lower alkyl, xe2x80x94C(O)O-lower alkyl, xe2x80x94C(O)O-lower alkyl-phenyl, lower alkynyl-phenyl, lower alkenyl-C(O)O-lower alkyl, lower alkenyl-cyano or phenyl, optionally substituted by halogen;
R3 is lower alkyl, or
phenyl, which is optionally substituted by lower alkyl, lower alkoxy, or halogen, or is thien-2-yl or fur-2-yl, which is optionally substituted by lower alkyl,
S-lower alkyl, halogen, lower alkoxy, xe2x80x94C(O)O-lower alkyl, xe2x80x94C(xe2x95x90CH2)-O-lower alkyl,
xe2x80x94(CH2)n-halogen, xe2x80x94(CH2).-OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F, or is 2,3-dihydro-benzo[1.4]dioxin-6-yl,
benzo[1.3]dioxol-5-yl,
isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl,
xe2x80x94C(xe2x95x90CH2)O-lower alkyl,
4,5-dihydrofuran-2-yl,
5,6-dihydro-4H-pyran-2-yl,
oxazol-2-yl,
benzofuranyl,
pyrazin-2-yl,
xe2x80x94Oxe2x80x94(CH2)nphenyl,
xe2x80x94Oxe2x80x94(CH2)n-pyridyl, optionally substituted by lower alkyl,
xe2x80x94Sxe2x80x94(CH2)n-pyridyl,
or pyrazol-1-yl, optionally substituted by lower alkyl or halogen;
R4/R5 are independently from each other hydrogen, xe2x80x94COxe2x80x94(CH2)n-phenyl, optionally substituted by halogen or xe2x80x94CH2N(R)(CH2)n-lower alkyl, or is phenyl, optionally substituted by lower alkoxy, or xe2x80x94C(O)-phenyl;
R is hydrogen or lower alkyl; or
A and R2 may be together with the two carbon atoms 
and
n is 0, 1, 2, 3, or 4;
m is 1 or 2;
and to their pharmaceutically acceptable salts.
A number of compounds of formula I are known, and are described in the following documents:
Tetrahedron Let., (1969), 247-250, used as intermediates;
Journal fuar prakt. Chemieg 320, (1978), 576-584, synthesis;
Synthesis, (1983), 402-404, used as intermediates;
Journ. of Heterocycl. Chem, 24, (1987), 1305-1307, synthesis;
Heterocycles, 36, (1993), 2281-2290, used for the treatment of AIDS;
EP 806418, used for the treatment of rotaviral diseases and acute gastroentritis;
JP 08134044, uses as antiviral agent; or
DE 24 59 629, used as hypotensive and analgesic agents.
It has now surprisingly been found that the compounds of general formula I are adenosine receptor ligands, and these compounds are therefore useful in the treatment of diseases, based on the modulation of the adenosine system.
Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and coenzym A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.
The receptors for adenosine have been classified as A1, A2A, A2B and A3 receptors, belonging to the family of G protein-coupled receptors. Activation of adenosine receptors by adenosine initiates signal transduction mechanism. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtypes has been classically characterised by the adenylate cyclase effector system, which utilises cAMP as a second messenger. The A1 and A3 receptors, coupled with G. proteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A2A and A2B receptors couple to GS proteins and activate adenylate cyclase, leading to an increase in cellular cAMP levels. It is known that the A1 receptor system include the activation of phospholipase C and modulation of both potassium and calcium ion channels. The A3 subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and so activates calcium ion channels.
The A1 receptor (326-328 amino acids) has been cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identity among the mammalian species. The A2A receptor (409-412 amino acids) has been cloned from canine, rat, human, guinea pig and mouse. The A2B receptor (332 amino acids) has been cloned from human and mouse with 45% homology of human A2B with human A1 and A2A receptors. The A3 receptor (317-320 amino acids) has been cloned from human, rat, dog, rabbit and sheep.
The A1 and A2A receptor subtypes are proposed to play complementary roles in adenosine""s regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (A1) or increase the oxygen supply (A2A) and so reinstate the balance of energy supply versus demand within the tissue. The actions of both subtypes is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischaemia, hypotension and seizure activity.
Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat A3 receptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the A3 receptor plays a role in mediating asthmatic attacks and other allergic responses.
Adenosine is also a neuromodulator, possessing global importance in the modulation of molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects. An increase in neurotransmitter release follows traumas such as hypoxia, ischaemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine A1 agonists which mimic the central inhibitory effects of adenosine may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitory neurons and inhibiting neuronal firing. Adenosine agonists therefore may be used as antiepileptic agents. Adenosine antagonists stimulate the activity of the CNS and have proven to be effective as cognition enhancers. Selective A2a-antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer""s disease and are useful as neuroprotective agents. Adenosine A2-receptor antagonists inhibit the release of dopamine from central synaptic terminals and reduce locomotor activity and consequently improve Parkinsonian symptoms. The central activities of adenosine are also implicated in the molecular mechanism underlying sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and substance abuse. Drugs acting at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants and antidepressants.
An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischaemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus have potential as cardioprotective agents.
Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds, which antagonise the renal affects of adenosine, have potential as renal protective agents. Furthermore, adenosine A3 and/or A2B antagonists may be useful in the treatment of asthma and other allergic responses.
Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:
Bioorganic and Medicinal Chemistry, 6, (1998), 619-641,
Bioorganic and Medicinal Chemistry, 6, (1998), 707-719,
J. Med. Chem., (1998), 41, 2835-2845,
J. Med. Chem., (1998), 41, 3186-3201,
J. Med. Chem., (1998), 41, 2126-2133,
J. Med. Chem., (1999), 42, 706-721,
J. Med. Chem., (1996), 39, 1164-1171 or
Arch. Pharm. Med. Chem., (1999), 332, 39-41.
The object of the present invention is the use of compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer""s disease, Parkinson""s disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardioprotective agents. The most preferred indications in accordance with the present invention are those, which base on the A2A receptor antagonistic activity and which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson""s disease. The invention relates also to the novel compounds disclosed in the present patent application per se, such as those specifically mentioned below. Furthermore, an object of the present invention are medicaments, based on a compound in accordance with formula I and their production.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a saturated straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1, 2, 3 or 4 carbon atoms.
As used herein, the term xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d denotes a unsaturated straight- or branched-chain alkyl group containing from 2 to 6 carbon atoms, for example, ethylen, propylen, isopropylen, n-butylen, i-butylen, 2-butylen, t-butylen and the like or ethynylen, propynylen, butyinylen and the like. Preferred lower alkyl groups are groups with 2, 3 or 4 carbon atoms.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group, containing 3, 4, 5 or 6 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues is as defined above, and which is attached via an oxygen atom.
The term xe2x80x9carylxe2x80x9d denotes preferrably a monocyclic aromatic ring, such as phenyl, optionally substituted by halogen.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Among the compounds of the present invention, preferred compounds include the compounds of Formula I, wherein R4 and R5 are both hydrogen and R2 is cyano, especially the compounds of formulas II, III and IV. 
Exemplary preferred compounds, showing selective activity on the A2A receptor, are compounds of formula II, wherein A is xe2x80x94NHxe2x80x94, for example the following compounds:
2-Amino-4-benzylamino-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-phenyl-propylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(2-phenylamino-ethylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(2-phenylamino-ethoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(2-phenoxy-ethylamino)-pyrimidine-5-carbonitrile,
2-amino-4-benzyl amino-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile,
6-furan-2-yl-5-nitro-N4-(3-phenyl-propyl)-pyrimidine-2,4-diamine,
2-amino-4-furan-2-yl-6-(2-methyl-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-methyl-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(4-methyl-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-methoxy-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(2-methoxy-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[(quinolin-2-yl-methyl)-amino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[(naphthalen-2-yl-methyl)-amino]-pyrimidine-5-carbonitrile,
(RS)-2-amino-4-furan-2-yl-6-[(1,2,3,4-tetrahydro-quinolin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(2-phenylsulfanyl-ethylamino)-pyrimidine-5-carbonitrile,
2-amino-4-(2-amino-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-(4-dimethylamino-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-[2-(4-chloro-phenylamino)-ethylamino]-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-(4-bromo-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[2-(pyridin-2-ylamino)-ethylamino]-pyrimidine-5-carbonitrile,
2-amino-4-[(benzo[1,3]dioxol-5a-ylmethyl)-amino]-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(4-trifluoromethyl-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-trifluoromethyl-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-(3,4-dimethyl-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[(4-(methyl-pyridin-2-yl-methyl)-amino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl6(-riloromty-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-(3-dimethyl-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[(5-methyl-pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[(isoquinolin-3-yl-methyl)-amino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-[(3-methyl-pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(4-vinyl-benzylamino)-pyrimidine-5-carbonitrile,
2-amino-4-(4-ethyl-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-[(3-chloro-5-trifluoromethyl-pyridin-2-yl-methyl)-amino]-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-[(3,5-dimethyl-pyridin-2-yl-methyl)-amino]-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-(4,5-dihydro-furan-2-yl)-6-[(4-methyl-pyridin-2-yl-methyl)-amino]-pyrimidine-5-carbonitrile or
2-amino-4-(2-bromo-benzylamino)-6-(5-bromo-furan-2-yl)-pyrimidine-5-carbonitrile.
Exemplary preferred compounds, showing selective activity on the A2A receptor, are compounds of formula II, wherein A is xe2x80x94Sxe2x80x94, for example the following compounds:
2-Amino-4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile,
2-amino-4-benzylsulfanyl-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-butylsulfanyl-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-ethylsulfanyl-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-phenyl-6-(3-phenyl-propylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-phenethylsulfanyl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-phenyl-propylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(pyridin-2-yl-methylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-(2-pyridin-2-yl-ethylsulfanyl)-6-thiophen-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-(4-methyl-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-(5-chloro-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-(5-bromo-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-(4-bromo-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-(5-cyanomethyl-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile,
2-amino-4-(4-cyano-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile or
2-amino-4-(5-difluoromethyl-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pryrimidine-5-carbonitrile.
Exemplary preferred compounds, showing selective activity on the A2A receptor, are further compounds of formula II, wherein A is xe2x80x94Oxe2x80x94, for example the following compounds:
2-amino-4-ethoxy-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-benzyloxy-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-phenethyloxy-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-phenyl-propoxy)-pyrimidine-5-carbonitrile,
2-amino-4-cyclohexyloxy-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-isopropoxy-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-phenethyloxy-6-phenyl-pyrimidine-5-carbonitrile,
2-amino-4-(pyridin-2-yl-6-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(6-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-methyl-furan-2-yl)-6-(6-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-methyl-furan-2-yl)-6-(pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-phenyl-allyloxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(naphthalen-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(3-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(5-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(isoquinolin-3-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan--2-yl-6-(4-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-furan-2-yl-6-(6-methyl-pyridin-3-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(3,5-dimethyl-pyridin-2-yl-methoxy)-6-furan-2-yl-pyrimidine-5-carbonitrile,
2-amino-4-(3-fluoro-phenyl)-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(4-methyl-furan-2-yl)-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-methyl-furan-2-yl)-6-(3-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(3,5-dimethyl-pyridin-2-yl-methoxy)-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile,
2-amino-4-(5-bromo-furan-2-yl)-6-(5-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-bromo-furan-2-yl)-6-(5-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-bromo-furan-2-yl)-6-(2-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-chloro-furan-2-yl)-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-chloro-furan-2-yl)-6-(3,5-dimethyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-chloro-furan-2-yl)-6-(3-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(5-chloro-furan-2-yl)-6-(5-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(4-bromo-furan-2-yl)-6-(5-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile,
2-amino-4-(4-bromo-furan-2-yl)-6-(3,5-dimethyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile or
2-amino-4-(4-bromo-furan-2-yl)-6-(3-methyl-pyridin-2-yl-methoxy)-pyrimidine-5-carbonitrile.
Preferred are further compounds of formula II, showing selective activity on the A2A receptor, wherein A is a bond, for example the following compounds:
2-Amino-4-furan-2-yl-6-piperidin-1-yl-pyrimidine-5-carbonitrile,
2-amino-6-furan-2-yl-pyrimidine-4,5-dicarbonitrile,
2-amino-4-furan-2-yl-6-phenyl-pyrimidine-5-carbonitrile,
(E)-2-amino-4-furan-2-yl-6-styryl-pyrimidine-5-carbonitrile or
2-amino-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-furan-2-yl-pyrimidine-5-carbonitrile.
Exemplary preferred compounds, showing selective activity on the A2A receptor, are compounds of formula III, wherein A is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, for example the following compounds:
6-Amino-2-furan-2-yl-4-(pyridin-2-yl-methoxy)-nicotinonitrile,
6-amino-2-furan-2-yl-4-(2-pyridin-2-yl-ethylsulfanyl)-nicotinonitrile,
6-amino-2-furan-2-yl-4-(4-trifluoromethyl-benzylamino)-nicotinonitrile,
6-amino-2-furan-2-yl-4-[(quinolin-2-yl-methyl)-amino]-nicotinonitrile,
6-amino-2-furan-2-yl-4-[(pyridin-2-yl-methyl)-amino]-nicotinonitrile,
6-amino-2-furan-2-yl-4-[(pyridin-2-yl-methyl)-amino]-nicotinonitrile,
6-amino-2-furan-2-yl-4-[(5-methyl-pyridin-2-yl-methyl)-amino]-nicotinonitrile,
6-amino-2-furan-2-yl-4-(3-methyl-pyridin-2-yl-methoxy)-nicotinonitrile or
6-amino-2-furan-2-yl-4-(2-pyridin-2-yl-ethoxy)-nicotinonitrile.
Preferred are further compounds of formula I, showing selective activity on the A2A receptor, wherein X and Y are nitrogen, A is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94Sxe2x80x94 and R2 is halogen or nitro, for example the following compounds:
5-Bromo-4-furan-2-yl-6-(pyridin-2-yl-methoxy)-pyrimidin-2-yl-amine,
5-bromo-6-furan-2-yl-N4-(3-phenyl-propyl)-pyrimidine-2,4-diamine,
5-bromo-4-furan-2-yl-6-(3-phenyl-propoxy)-pyrimidin-2-yl-amine,
4-furan-2-yl-5-iodo-6-(3-phenyl-propoxy)-pyrimidin-2-yl-amine,
5-bromo-4-furan-2-yl-6-phenethylsulfanyl-pyrimidin-2-yl-amine,
5-bromo-4-furan-2-yl-6-(3-phenyl-allyloxy)-pyrimidin-2-yl-amine,
4-benzyloxy-6-furan-2-yl-5-nitro-pyrimidin-2-yl-amine,
5-chloro-6-furan-2-yl-N4-(3-phenyl-propyl)-pyrimidine-2,4-diamine,
5-chloro-4-furan-2-yl-6-(3-phenyl-propoxy)-pyrimidin-2-yl-amine,
5-chloro-4-furan-2-yl-6-phenethyloxy-pyrimidin-2-yl-amine,
4-benzylsulfanyl-5-chloro-6-furan-2-yl-pyrimidin-2-yl-amine,
4-furan-2-yl-5-iodo-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-yl-amine,
5-bromo-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-yl-amine or
5-chloro-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-yl-amine.
Further preferred are compounds of formula I, showing selective activity on the A2A receptor, wherein X is xe2x95x90C(cyano)xe2x80x94, Y is xe2x80x94Nxe2x95x90, A is xe2x80x94Sxe2x80x94 and R2 is CN, for example the following compound:
2-Amino-6-benzylsulfanyl-4-thiophen-2-yl-pyridine-3,5-dicarbonitrile.
Exemplary preferred compounds, showing selective activity on the A2A receptor, are compounds of formula I, wherein X and Y are nitrogen, A is xe2x80x94Sxe2x80x94, R2 is cyano and R5 is xe2x80x94C(O)-phenyl, for example the following compound:
N[5-Cyano-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-yl]-benzamide.
Additional preferred compounds include compounds having the structure of formula II 
wherein A is xe2x80x94NH and R1 and R3 are as defined above. The more preferred compounds of formula II, include, but are not limited to, compounds wherein R1 is selected from the group consisting of lower alkyl, cycloalkyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)n-phenyl substituted by 1 or 2 substituents selected from the group consisting of hydroxy, lower alkoxy, lower alkyl, CF3-lower alkenyl, halogen, CF3, OCF3, and amino,
xe2x80x94(CH2)n-pyridin-2-yl,
xe2x80x94(CH2)n-pyridin-2-yl, substituted by 1 or 2 substituents, selected from lower alkyl and CF3,
xe2x80x94(CH2)n(CHxe2x95x90CH)m-phenyl,
xe2x80x94(CH2)n-isoquinolin-3-yl,
xe2x80x94(CH2)n-quinolin-2-yl,
xe2x80x94(CH2)n-naphthyl,
xe2x80x94(CH2)n-3,4-dihydro-1H-isoquinolin-2-yl,
xe2x80x94(CH2)n-benzo[1,3]dioxolyl,
xe2x80x94(CH2)n-isoquinolin-3-yl
xe2x80x94(CH2)n-1,2,3,4-tetrahydro-quinolin-2-yl,
xe2x80x94(CH2)n-1,2,3,4-tetrahydro-quinolin-2-yl, substituted by lower alkyl. In this more preferred series of the structure of formula II, R3 is selected from the group consisting of fur-2yl, fur-2yl, substituted by lower alkyl, and 4,5-dihydrofuran-2-yl; and wherein n is 0, 1, 2, 3 or 4; m is 1 or 2; and pharmaceutically acceptable salts thereof.
Additional more preferred compounds having the structure of formula II include compounds wherein A is xe2x80x94Oxe2x80x94 and R1 and R3 are as defined above. These compounds include, but are not limited to, R1 being selected from the group consisting of lower alkyl, cycloalkyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)n-phenyl substituted by 1 or 2 substituents selected from the group consisting of lower alkoxy, lower alkenyl, halogen, xe2x80x94(CH2)nxe2x80x94pyridin-2-yl, xe2x80x94(CH2)n-pyridin-3-yl. xe2x80x94(CH2)n-pyridin-2-yl, and xe2x80x94(CH2)n-pyridin-3-yl substituted by 1 or 2 substituents, selected from lower alkyl, xe2x80x94(CH2)n(CHxe2x95x90CH)m-phenyl, xe2x80x94(CH2)n-isoquinolin-3-yl, and xe2x80x94(CH2)n-naphthyl. R3 is selected from the group consisting of phenyl, phenyl substituted by halogen, thien-2yl, fur-2yl, thien-2yl and fur-2yl substituted by lower alkyl, and halogen; and wherein N is 0, 1, 2, 3 or 4; and m is 1 or 2; and pharmaceutically acceptable salts of the compounds.
Yet additional more preferred compounds related to formula II include, but are not limited to, compounds wherein A is xe2x80x94Sxe2x80x94, and R1 and R3 are as defined above. Compounds, and their pharmaceutically acceptable salts in this more preferred series having the structure of formula II include, but are not limited to, RI being selected from the group consisting of lower alkyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)n-phenyl substituted by lower alkyl, xe2x80x94(CH2)n-pyridin-2-yl substituted by lower alkyl; and wherein R3 is selected from the group consisting of lower alkyl, thiene-2yl, fur-2yl, fur-2yl substituted by halogen, xe2x80x94(CH2)nxe2x80x94cyano, CHF2, and 2,3-dihydro-benzo[1.4]diosin-6-yl; and wherein n is 0, 1, 2, 3 or 4 and m is 1 or 2.
An additional series of more preferred compounds, and the pharmaceutically acceptable salts thereof, having the structure of formula II include, but are not limited to, A is a bond and R1 and R3 are as defined above. These compounds include R1 being selected from the group including cyano, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)n(CHxe2x95x90CH)m-phenyl, xe2x80x94(CH2)n-piperidin-1-yl, and xe2x80x94(CH2)n-3,4-dihydro-1H-isoquinolin-2-yl. In this series, R3 is -fur-2yl; and n=0 and m=1.
Yet more preferred compounds include compounds having the structure of formula III 
where A is selected from the group consisting of xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94 and R1 and R3 are as above. These compounds having the structure of formula III and their pharmaceutically salts further include R1 being selected from the group consisting of xe2x80x94(CH2)n-phenyl substituted by CF3, xe2x80x94(CH2)n-pyridin-2-yl, substituted by lower alkyl, and xe2x80x94(CH2)n-quinolin-2-yl substituted by lower alkyl, wherein n=0, 1, 2; R3 is fur-2yl.
The compounds of formula I may be prepared in accordance with the following schemes 1-20:
Preparation of compounds of Formula I wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is hydrogen, alkyl or aryl, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula I, wherein A has the above mentioned definition, is from intermediates of formula (5), the preparation of which is shown in Reaction Scheme I below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R2 is hydrogen, alkyl or aryl, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (2)
The starting ketone of formula (1) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art.
To prepare compounds of formula (2), a ketone of formula (1) is sequentially treated with a strong non-aqueous base, preferably sodium hydride, and with carbon disulphide, in a polar non-protic solvent, preferably dimethyl sulfoxide, at room temperature for about 1-2 hours, preferably 2 hours, and then treated with methyl iodide at room temperature for about 2-16 hours, preferably 16 hours. The product of formula (2) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (2) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (4)
The inorganic acid addition salts of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The compounds of formula (4) are prepared by treating compounds of formula (2) with a slight excess of the guanidine compounds of formula (3) in a polar non-protic solvent, preferably dimethylformamide, containing a base, preferably sodium hydride, at reflux for 18-96 hours, preferably 90 hours. The product of formula (4) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (4) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (5)
The methylsulfanyl-pyrimidine derivative of formula (4) maybe converted to the corresponding methanesulfinyl-pyrimidine derivative of formula (5) by reacting a compound of formula (4) with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an inert organic solvent, preferably dichloromethane, at room temperature. The product of formula (5) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (5) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is hydrogen, alkyl or aryl, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-Syl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula I, wherein A has the above mentioned definition, is by treatment of a compound of formula (5) with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at a temperature between room temperature and the reflux temperature of the solvent, preferably about 80xc2x0 C., for 18-48 hours, preferably 48 hours. The product of Formula I wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is hydrogen, alkyl or aryl, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is alkyl, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
An alternative method of preparation of compounds of Formula I, wherein A has the above mentioned definition, is from intermediates of formula (11), the preparation of which is shown in Reaction Scheme II below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R2 is alkyl, R3i phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, R4 and R5 are hydrogen or lower alkyl and R is lower alkyl.
Preparation of Compounds of Formula (9)
The starting xcex2-ketoester of formula (7) and alkyl halides of formula (8) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art.
To prepare compounds of formula (9), a xcex2-ketoester of formula (7) is reacted with a strong non-aqueous base, preferably lithium hexamethyldisilazide, in an ethereal solvent (for example, tetrahydrofuran, dioxane, diethyl ether, or 1,2-dimethoxyethane, preferably tetrahydrofuran), at a temperature of xe2x88x9278xc2x0 C. for about 30-60 minutes, preferably 30 minutes, after which time a slight excess of an alkyl halide of formula (8), preferably an alkyl bromide, is added, and the mixture allowed to warm gradually to room temperature over about 12-16 hours. The product of formula (9) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (10)
The carbonate salts of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The compounds of formula (10) are prepared by treating compounds of formula (9) with a guanidine carbonate compound of formula (3) in a polar solvent, preferably ethanol, at reflux for 1-18 hours, preferably 16 hours. The product of formula (10) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (10) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (11)
A compound of formula (10) is reacted with an alkanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and an excess of a non-nucleophilic base, preferably 2,6-di-tert-butylpyridine, in an organic solvent, preferably dichloromethane, at a temperature between 0xc2x0 C. and room temperature for about 16 hours. The product of formula (11) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is alkyl, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (11) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 16 hours. The product of Formula I, wherein A has the above mentioned definition, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula I wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
An alternative method of preparation of compounds of Formula I, wherein A is as defined above, is from intermediates of formula (12), formula (13), formula (14) or formula (15), the preparation of which is shown in Reaction Scheme III below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, R4 and R5 are hydrogen or lower alkyl and R is lower alkyl.
Preparation of Compounds of Formula (12)
The starting xcex2-ketoester of formula (7) and the carbonate salts of guanidine or of substituted guanidine compounds of formula (3) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art.
The compounds of formula (12) are prepared by treating compounds of formula (7) with a guanidine carbonate compound of formula (3) in a polar solvent, preferably ethanol, at reflux for 1-18 hours, preferably 16 hours. The product of formula (12) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (12) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I wherein A is oxygen, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (12) is reacted with an excess of an appropriate alkyl halide of formula (8), such as a primary or secondary aliphatic halide, preferably an aliphatic bromide or a benzylic bromide, which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in a polar solvent, preferably dimethylformamide, in the presence of an excess of a base, preferably cesium carbonate, at room temperature or above, preferably at about 100xc2x0 C. for 1-18 hours, preferably for 16 hours. The product of Formula I where A is oxygen, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (13)
The compound of formula (12) is reacted with a chlorinating agent, preferably phosphorus oxychloride, preferably in the absence of solvent. The reaction is conducted at the reflux temperature for about 1-3 h, preferably about one and a half hours. The product of formula (13) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (13) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 18 hours. The product of Formula I where A is nitrogen, oxygen, or sulfur, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (14)
A compound of formula (12) is reacted with an alkanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and an excess of a non-nucleophilic base, preferably 2,6-di-tert-butylpyridine, in an organic solvent, preferably dichloromethane, at a temperature between 0xc2x0 C. and room temperature for about 16 hours. The product of formula (14) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (14) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 18 hours. The product of Formula I where A is nitrogen, oxygen, or sulfur, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (15)
A compound of formula (13), or a compound of formula (14), is reacted with an excess of alkali metal thiolate, preferably sodium thiolate, in a polar organic solvent, preferably ethanol. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., and preferably for about 16 h. The product of formula (15) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (15) may, however, be additionally purified by means of recrystallisation.
Alternative preparation of compounds of Formula I, wherein A is sulfur, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (15) is reacted with an excess of an appropriate organic halide of formula (8), such as a primary or secondary aliphatic halide, preferably an aliphatic bromide or a benzylic bromide, which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of a base, preferably sodium methylate or sodium, ethylate, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 2 hours. The product of Formula I where A is sulfur, X and Y are nitrogen, R2 is hydrogen, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is fluoro, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-Syl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen and R2 and R3 are as defined above, is from intermediates of formula (20), the preparation of which is shown in Reaction Scheme IV below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, R4 and R5 are hydrogen or lower alkyl and R is lower alkyl.
Preparation of Compounds of Formula (16)
The starting xcex2-ketoester of formula (7) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art.
To prepare compounds of formula (16), a P-ketoester of formula (7) is reacted with a fluorinating agent, preferably 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis(tetrafluoroborate), in an organic solvent, preferably acetonitrile, at room temperature for about 1-4 days, preferably 4 days. The product of formula (16) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula (16)
The starting a-fluoroester of formula (17) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art.
In an alternative method to prepare compounds of formula (16), a xcex1-fluoroester of formula (17) is reacted with a strong non-aqueous base, preferably lithium diisopropylamide, in an ethereal solvent (for example, tetrahydrofuran, dioxane, diethyl ether, or 1,2-dimethoxyethane, preferably diethyl ether), at a temperature of xe2x88x9278xc2x0 C. for about 30-60 minutes, preferably 30 minutes, after which time about 1 equivalent of an acyl chloride of formula (18) is added, and the mixture allowed to warm gradually to 0xc2x0 C. The product of formula (16) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (19)
The carbonate salts of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The compounds of formula (19) are prepared by treating compounds of formula (16) with a slight excess of the guanidine carbonate compounds of formula (3) in a polar solvent, preferably ethanol, at reflux for 1-18 hours, preferably 4 hours. The product of formula (19) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (19) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (20)
A compound of formula (19) is reacted with an alkanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and an excess of a non-nucleophilic base, preferably 2,6-di-tert-butylpyridine, in an inert organic solvent, preferably dichloromethane, at a temperature between 0xc2x0 C. and room temperature for about 16 hours. The product of formula (20) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula L wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is fluoro, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (20) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 18 hours. The product of Formula I wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is fluoro, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofaranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is chloro, bromo or iodo, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula I, wherein A, X, Y, R2 and R3 are defined as above, is from intermediates of formula (23), the preparation of which is shown in Reaction Scheme V below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R2 is chloro, bromo or iodo, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (22)
The compounds of formula (4), which may be prepared as depicted in Reaction Scheme I, may be converted to compounds of formula (22) by reacting a compound of formula (4) with a halogenating agent, preferably an N-halosuccinimide of formula (21), where R2 is chloro, bromo or iodo, in an organic solvent, preferably acetic acid, at a temperature between room temperature and 50xc2x0 C., preferably room temperature in the case of the bromo and iodo derivatives, and preferably 50xc2x0 C. in the case of the chloro derivatives, for about 16-72 hours. The product of formula (22) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (23)
The compounds of formula (22) may be converted to compounds of formula (23) by reacting a compound of formula (22) with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an inert organic solvent, preferably dichloromethane, at room temperature. The product of formula (23) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (23) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is chloro, bromo or iodo, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of derivatives of Formula I wherein A, X, Y, R2 and R3 are as defined above, is by treatment of a compound of formula (23) with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of Formula I wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, K is chloro, bromo or iodo, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Conversion of Compounds of Formula I to Other Compounds of Formula I
Miscellaneous routes to compounds of Formula I from compounds of Formula I where X and Y are nitrogen and R2 is iodo are shown in Reaction Scheme VI: 
wherein A is nitrogen, oxygen or sulfur, R1 and R3 are as defined above, R4, R5, R7, R8 and R9 are hydrogen or lower alkyl, R10 is aryl, R11 is aryl or alkenyl R is alkyl or benzyl and Z is an electron-withdrawing group, such as CN or CO2R.
Preparation of Compounds of Formula I, Wherein X and Y are Nitrogen and R2 is Aryl or Alkenyl
Boronic acid derivatives of formula (24) where R11l is aryl or alkenyl may be obtained commercially, or may be prepared by methods well known in the art. A compound of Formula I where X and Y are nitrogen and R2 is iodo is reacted with a boronic acid derivative of formula (24) in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 6-18 hours, preferably about 16 hours. The product of Formula I where X and Y are nitrogen and R2 is aryl or alkenyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula I, Wherein X and Y are Nitrogen and R2 is Alkenyl
Trialkylstannane derivatives of formula (25), wherein R is methyl or n-butyl and R7, R8 and R9 are independently H or lower alkyl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of Formula I where X and Y are nitrogen and R2 is iodo is reacted with a trialkylstannane derivative of formula (25) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine). The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 14-36 hours, preferably about 16 hours. The product of Formula I where X and Y are nitrogen and R2 is alkenyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula I, Where X and Y are Nitrogen and R2 is Alkyl
A compound of Formula I, wherein X and Y are nitrogen and R2 is alkenyl is reacted with hydrogen gas in an organic solvent (for example 1,2-dimethoxyethane, tetrahydrofuran, dioxane or ethanol, preferably a mixture ethanol) containing a hydrogenation catalyst, preferably 10% palladium on charcoal. The reaction is carried out at room temperature at a pressure of 1 atmosphere or above, preferably at one atmosphere, for about 2-36 hours, preferably about 16 hours. The product of Formula I where X and Y are nitrogen and R2 is alkyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula I, Wherein X and Y are Nitrogen and R2 is alkenyl
Alkene derivatives of formula (26), where in Z is CO2R or CN and R is alkyl or benzyl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of Formula I where X and Y are nitrogen and R2 is iodo is reacted with an alkene derivative of formula (26) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), and an inorganic base, preferably cesium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 8-18 hours, preferably about 12 hours. The product of Formula I where X and Y are nitrogen and R2 is alkenyl is isolated by conventional means, and preferably, purified by chromatography or recrystallisation.
Preparation of Compounds of Formula I, Wherein X and Y are Nitrogen and R2 is Acetyl
Compounds of Formula I, wherein X and Y are nitrogen and R2 is acetyl, can be made from intermediates of formula (28), which may themselves be prepared from compounds of Formula I where X and Y are nitrogen and R2 is iodo.
Preparation of Compounds of Formula (28)
Trialkylstannane derivatives of formula (27), wherein R is methyl or n-butyl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of Formula I where X and Y are nitrogen and R2 is iodo is reacted with a trialkylstannane derivative of formula (27) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 10-18 hours, preferably about 16 hours. The product of formula (28) is isolated by conventional means, and preferably reacted in the next step with no further purification.
Preparation of Compounds of Formula I Wherein X and Y are Nitrogen and R2 is Acetyl
A compound of formula (28) is reacted with a dilute aqueous solution of a Bronsted acid, preferably hydrochloric acid, in an aqueous solvent, preferably a mixture of tetrahydrofuran and water. The reaction is preferably carried out at room temperature for about 18-48 hours, preferably 44 hours. The product of Formula I where X and Y are nitrogen and R2 is acetyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula I, Wherein X and Y are Nitrogen and R2 is Alkoxycarbonyl
A compound of Formula I, wherein X and Y are nitrogen and R2 is iodo, is reacted with carbon monoxide gas in an alcoholic solvent of formula (29) (for example methanol, ethanol, benzyl alcohol, or a solution of one of these alcohols in dimethylformamide), containing a palladium catalyst, preferably tris(dibenzylidineacetone)dipalladium chloroform complex, a catalytic amount of a monodentate ligand, preferably triphenylarsine, and an excess of an organic base, preferably triethylamine. The reaction is carried out at a pressure of 1-20 atmospheres, preferably 1 atmosphere, and at a temperature above room temperature, preferably about 100-110xc2x0 C., for about 8-18 hours, preferably about 12 hours. The product of Formula I where X and Y are nitrogen and R2 is alkoxycarbonyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula I Where X and Y are Nitrogen and R2 is Alkynyl
Alkyne derivatives of formula (30), wherein R10 is aryl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of Formula I where X and Y are nitrogen and R2 is iodo is reacted with an alkene derivative of formula (30) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably tetrahydrofuran), containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride, a copper co-catalyst, preferably copper(I) iodide, and an excess of an organic base, preferably triethylamine. The reaction is preferably carried out at room temperature for about 16-96 hours, preferably about 18 hours. The product of Formula I where X and Y are nitrogen and R2 is alkynyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is nitro, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
One method of preparation of compounds of Formula I, wherein A, X, Y, R2 and R3 is defined above, and R4 and R5 are hydrogen is from intermediates of formula (36), the preparation of which is shown in Reaction Scheme VII below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl-pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
Preparation of Compound of Formula (32)
2-Amino-6-chloro-4-oxo-3,4-dihydro-pyrimidine, a compound of formula (31) wherein R4 and R5 are hydrogen, which may be obtained commercially, for example from Fluka Chemie AG, is reacted with a nitrating mixture, preferably a mixture of concentrated sulphuric and nitric acids, preferably in the absence of added solvent. The reaction is conducted at a temperature of about 20-40xc2x0 C., for about 30-90 minutes. The product of formula (32), 2-amino-6-chloro-5-nitro-4-oxo-3,4-dihydro-pyrimidine, is isolated by conventional means, and preferably purified by means of recrystallisation.
Preparation of Compounds of Formula (35)
Boronic acid derivatives of formula (33), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, may be obtained commercially, or may be prepared by methods well known in the art. The compound of formula (32), 2-amino-6-chloro-5-nitro-4-oxo-3,4-dihydro-pyrimidine, is reacted with a boronic acid derivative of formula (33) in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably palladium tetrakis (triphenylphosphine), and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 2-8 hours, preferably about 4 hours. The product of formula (35) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula (35)
Trialkylstannane derivatives of formula (34), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4.5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R is methyl or n-butyl, may be obtained commercially, or may be prepared by methods well known in the art. The compound of formula (32), 2-amino-6-chloro-5-nitro-4-oxo-3,4-dihydro-pyrimidine, is reacted with a trialkystannane derivative of formula (34) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine). The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 10-18 hours, preferably about 16 hours. The product of formula (35) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula (36)
A compound of formula (35) is reacted with an alkanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and an excess of a non-nucleophilic base, preferably 2,6-di-tert-butylpyridine, in an organic solvent, preferably dichloromethane, at a temperature between 0xc2x0 C. and room temperature for about 16 hours. The product of formula (36) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is nitro, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
The compound of formula (36) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1.8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 16 hours. The product of Formula I wherein A is nitrogen, oxygen or sulfur, X and Y are nitrogen, R2 is nitro, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Conversion of compounds of Formula I, wherein Axe2x80x94R1 is methylsulfanyl and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, pyrazin-2-yl, or pyrazol-1-yl (optionally substituted by lower alkyl or halogen), to other compounds of Formula I wherein A is nitrogen, oxygen or sulfur and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)n-OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, pyrazin-2-yl, or pyrazol-1-yl (optionally substituted by lower alkyl or halogen).
A method of converting compounds of Formula I as mentioned above, is shown in Reaction Scheme VIII: 
wherein A is nitrogen, oxygen or sulfur, X, Y, R1 and R2 are as defined above, R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, pyrazin-2-yl, or pyrazol-1-yl (optionally substituted by lower alkyl or halogen), and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (37)
A compound of Formula I, wherein Axe2x80x94R1 is methylsulfanyl and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, pyrazin-2-yl, or pyrazol-1-yl (optionally substituted by lower alkyl or halogen), is reacted with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an inert organic solvent, preferably dichloromethane, at room temperature. The product of formula (37), a methanesulfinyl-pyrimidine derivative, is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (37) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, pyrazin-2-yl, or pyrazol-1-yl (optionally substituted by lower alkyl or halogen).
The methanesulfinyl-pyrimidine derivative of formula (37) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or, secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of Formula I where A is nitrogen, oxygen or sulfur and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, pyrazin-2-yl, or pyrazol-1-yl (optionally substituted by lower alkyl or halogen), is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is cyano or CO2R (where R is alkyl or benzyl), R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula I, wherein Axe2x80x94R1, X, Y, R2 and R3 is defined as mentioned above, is from intermediates of formula (39), the preparation of which is shown in Reaction Scheme IX below. 
wherein R2 is cyano or CO2R (where R is alkyl or benzyl), R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo [1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (39)
The starting ketones of formula (38) may be obtained commercially, for example from Avocado Research Chemicals Limited, or may be prepared according to methods well known in the art.
To prepare compounds of formula (39), an ketone of formula (38) is reacted with N,N-dimethylformamide dimethyl acetal, preferably in the absence of solvent, at room temperature for about 1-8 hours, preferably 2 hours. The product of formula (39) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (39) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is cyano, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The carbonate salts of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The 2-amino-pyrimidine-5-carbonitrile derivative of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is cyano, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is prepared by treating compounds of formula (39) with an excess of a guanidine carbonate compound of formula (3) in a polar solvent, preferably methanol, containing an excess of base, preferably sodium methylate, at room temperature for 1-4 hours, preferably about 2 hours. The product of Formula I is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, where Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is CO2R (where R is alkyl or benzyl), and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The inorganic acid addition salts, such as the nitrate salts, of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The 5-alkoxycarbonyl-2-amino-pyrimidine derivative of Formula I, wherein the definitions are given above, is prepared by treating compounds of formula (39) with a slight excess of a guanidine nitrate compound of formula (3) in a polar solvent, dimethylformamide, containing a slight excess of base, preferably sodium acetate or triethylamine, at 90xc2x0 C. for 12-36 hours, preferably about 18 hours. The product of Formula I is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is hydrogen, chloro, bromo or iodo, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula I, with the above mentioned definitions is from intermediates of formula (41), the preparation of which is shown in Reaction Scheme X below. 
wherein R2 is hydrogen, chloro, bromo or iodo, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3)]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (41) The starting methylketone of formula (40) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art.
To prepare compounds of formula (41), a methylketone of formula (40) is reacted with N,N-dimethylformamide dimethyl acetal in N,N-dimethylformamide at reflux for about 16 hours. The product of formula (41) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (42)
A compound of formula (41) is reacted with a chlorinating agent, preferably phosphorus oxychloride, in on organic solvent, preferably dichloromethane, at room temperature for 1 hour. The solvent is then removed in vacuo and the residue is reacted with sodium hexafluorophosphate in an alcoholic solvent, preferably methanol, at 0xc2x0 C. for about 15 minutes. The product of formula (42) is isolated by conventional means, and preferably used in the next reaction without further purification.
Preparation of Compounds of Formula (43)
A compound of formula (42) is reacted with an excess of a salt of a secondary alkyl amine, preferably dimethylamine hydrochloride, in an alcoholic solvent, preferably ethanol, containing a base, preferably sodium ethylate. The reaction is preferably performed at room temperature for 1-18 hours, preferably 16 hours. The product of formula (43) is isolated by conventional means, and preferably used in the next reaction without further purification.
Preparation of compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is hydrogen, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The carbonate salts of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The 2-amino-pyrimidine derivative of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is hydrogen, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl is prepared by treating compounds of formula (43) with a slight excess of the guanidine carbonate compounds of formula (3) in a polar non-protic solvent, preferably dimethylformamide, containing an excess of base, preferably sodium hydride. The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent, preferably about 100xc2x0 C., for 1-16 hours, preferably about 1 hours. The product of Formula I is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is hydrogen, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The carbonate salts of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The 2-amino-pyrimidine derivative of Formula I, wherein the definitions are given above, is prepared by treating compounds of formula (41) with an excess of the guanidine carbonate compounds of formula (3) in a polar solvent, preferably methanol, containing an excess of base, preferably sodium methylate, at a temperature between room temperature and the reflux temperature of the solvent, preferably about 80xc2x0 C., for about 2 hours. The product of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is hydrogen, chloro, bromo or iodo, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is chloro, bromo or iodo, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
Compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is hydrogen, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, may be converted to the corresponding 5-halo derivatives of Formula I where R2 is chloro, bromo or iodo, by reacting a compound of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen, R2 is hydrogen, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, with a halogenating agent, preferably an N-halosuccinimide of formula (21), where R2 is chloro, bromo or iodo, in an organic solvent, preferably acetic acid, at room temperature for about 16-72 hours. The product of formula I is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Conversion of compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen, and R2 is iodo, to other compounds of Formula I, where Axe2x80x94R1 is hydrogen and X and Y are nitrogen.
Miscellaneous routes to compounds of Formula I, where in Axe2x80x94R1 is hydrogen and X and Y are nitrogen, from compounds of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen and R2 is iodo are shown in Reaction Scheme XI: 
wherein R3 is as defined above, R4 and R5 are hydrogen or lower alkyl, R is alkyl or benzyl, and Z is an electron-withdrawing group such as CN or CO2R.
Preparation of Compounds of Formula I, Wherein Axe2x80x94R1 is Hydrogen, X and Y are Nitrogen and R2 is aryl or Alkenyl
Boronic acid derivatives of formula (24), wherein R11 is aryl or alkenyl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen and R2 is iodo is reacted with a boronic acid derivative of formula (24) in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably palladium tetrakis(triphenyl-phosphine), and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 6-18 hours, preferably about 16 hours. The product of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen and R2 is aryl or alkenyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula I, Wherein Axe2x80x94R1 is Hydrogen, X and Y are Nitrogen and R2 is Alkenyl
Alkene derivatives of formula (26), wherein Z is CO2R or CN and R is alkyl or benzyl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen and R2 is iodo is reacted with an alkene derivative of formula (26) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), and an inorganic base, preferably cesium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 8-18 hours, preferably about 12 hours. The product of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen and R2 is alkenyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula I, Wherein Axe2x80x94R1 is Hydrogen X and Y are Nitrogen and R2 is Alkoxycarbonyl
A compound of Formula I, wherein Axe2x80x94R1 is hydrogen, X and Y are nitrogen and R2 is iodo, is reacted with carbon monoxide gas in an alcoholic solvent of formula (29) (for example methanol, ethanol, benzyl alcohol, or a solution of one of these alcohols in dimethylformamide), containing a palladium catalyst, preferably tris(dibenzylidine-acetone)dipalladium chloroform complex, a catalytic amount of a monodentate ligand, preferably triphenylarsine, and an excess of an organic base, preferably triethylamine. The reaction is carried out at a pressure of 1-20 atmospheres, preferably 1 atmosphere, and at a temperature above room temperature, preferably about 100-110xc2x0 C., for about 8-18 hours, preferably about 12 hours. The product of Formula I where Axe2x80x94R1 is hydrogen, X and Y are nitrogen and R2 is alkoxycarbonyl is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of compounds of Formula I, wherein A is nitrogen, oxygen or sulfur, X is Cxe2x80x94CN, Y is nitrogen, R2 is cyano, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen p
One method of preparation of compounds of Formula I as mentioned above is from intermediates of formula (47), the preparation of which is shown in Reaction Scheme XII below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)nxe2x80x94lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol 5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofaranyl, or pyrazin-2-yl.
Preparation of Compounds of Formula (46) and Formula (47)
An aldehyde of formula (45), which may be obtained commercially or may be prepared according to methods well known in the art, is reacted with one equivalent of 2-cyanothioacetamide of formula (44) and one equivalent of malonitrile. The reaction is carried out in a polar organic solvent (for example ethanol, dimethylformamide, or a mixture of ethanol and dimethylformamide, preferably a mixture of ethanol and dimethylformamide) containing a catalytic amount of an amine base (for example piperidine, triethylamine or morpholine, preferably piperidine). The reaction is carried out at a temperature between 0xc2x0 C. and 100xc2x0 C., preferably about 0xc2x0 C., for about 30 minutes to 2 hours, preferably about 1 hour. The products of formula (46), a 2,6-diamino-4H-thiopyran-3,5-dicarbonitrile derivative, and of formula (47), a 6-amino-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile derivative, are isolated by conventional means, and preferably purified by chromaotography or recrystallisation. The ratio between the amount of product of formula (46) which is obtained and the amount of product of formula (47) which is obtained is dependent on the nature of the substituent R3.
Conversion of Compounds of Formula (46) to Compounds of Formula (47)
A 2,6-diamino-4H-thiopyran-3,5-dicarbonitrile derivative of formula (46) may be converted to a 6-amino-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile derivative of formula (47) by treatment with an excess of concentrated aqueous ammonia. The reaction is carried out in an alcoholic solvent, such as methanol or ethanol, at room temperature for about 2-4 hours. The product of formula (47) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula (48)
A compound of formula (47) is reacted with an excess of methyl iodide. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of about one equivalent of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably room temperature, for 1-18 hours, preferably about 2 hours. The product of formula (48) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (49)
A methylsulfanyl-pyridine compound of formula (48) may be converted to the methanesulfinyl-pyridine derivative of formula (49) by reacting a compound of formula (48) with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an organic solvent, preferably dichloromethane, at room temperature. The product of formula (49) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (49) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula I, where in A is nitrogen, oxygen or sulfur, X is Cxe2x80x94CN, Y is nitrogen, R2 is cyano, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen.
A compound of formula (49) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature of the solvent, for 1-18 hours, preferably 1 hour. The product of Formula I where A is nitrogen, oxygen or sulfur, X is Cxe2x80x94CN, Y is nitrogen, R2 is cyano, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula I, wherein A is sulfur, X is Cxe2x80x94CN, Y is Nitrogen, R2 is cyano, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen.
An alternative method of converting a compound of formula (47) to a compound of Formula I as mentioned above is by reaction of the compound of formula (47) with an excess of an appropriate organic halide of formula (8), such as a primary or secondary aliphatic halide, preferably an aliphatic bromide or a benzylic bromide, which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of an excess of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 1 hour. The product of Formula I where A is sulfur, X is Cxe2x80x94CN, Y is nitrogen, R2 is cyano, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula II, wherein the substituents are defined above, is from intermediates of formula (52), of formula (53) or of formula (54), the preparation of which is shown in Reaction Scheme XIII below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5y-1, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (51)
The starting xcex1-cyanoketone of formula (50) may be obtained commercially, for example from Avocado Research Chemicals Limited, or may be prepared according to methods well known in the art.
Compounds of formula (51) may be prepared by using the method of Rudorf and Augustin in DD 119041 and Phosphorus and Sulfur, 1981, 9, 329, in which an xcex1-cyanoketone of formula (50) is sequentially treated with a strong non-aqueous base, preferably sodium hydride, and with carbon disulphide, in a polar non-protic solvent, preferably dimethyl sulfoxide, at room temperature for about 1-2 hours, preferably 2 hours, and then treated with methyl iodide at room temperature for about 2-16 hours, preferably 2 hours. The product of formula (51) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (51) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (52)
The inorganic salts of guanidine or of substituted guanidine compounds of formula (3) are commercially available, or may be prepared according to methods well known in the art.
The compounds of formula (52) are prepared according to the method of Rudorf and Augustin in J. Prakt. Chem., 1978, 320, 576, in which compounds of formula (51) are treated with a slight excess of the guanidine compounds of formula (3) in a polar non-protic solvent, preferably dimethylformamide, containing a base, preferably triethylamine or sodium hydride, at reflux for 1-8 hours, preferably 1 hour in the case where sodium hydride is used, and preferably 6 hours in the case where triethylamine is used. The product of formula (52) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (52) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (53) and Formula (54)
The methylsulfanyl-pyrimidine compound of formula (52) is reacted with an oxidising agent, preferably meta-chloroperbenzoic acid or 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an organic solvent, preferably dichloromethane, at room temperature to give a product of formula (53) or formula (54), whereby in the case of using meta-chloroperbenzoic acid the methanesulfonyl-pyrimidine derivative of formula (53) is preferentially formed, and in the case of using 3-phenyl-2-(phenylsulfonyl)oxaziridine the methanesulfinyl-pyrimidine derivative of formula (54) is preferentially formed. The products of formula (53) or of formula (54) are isolated by conventional means, and preferably reacted in the next step without further purification. The products of formula (53) or formula (54) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula II as mentioned above is by treatment of compounds of formula (53) with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 18 hours. The product of Formula II where A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
An alternative method of preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is by treatment compounds of formula (54) with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of Formula II where A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Yet another method of preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is by treatment of compounds of formula (52) with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary amine which is preferably used in excess in the absence of an added base; an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane. These reactions are carried out at room temperature or above, preferably at the reflux temperature of the solvent, for 16-48 hours, preferably for 18 hours. The product of Formula II where A is nitrogen, oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation. Additionally, if the nucleophile of formula (6) used is a primary or secondary aliphatic amine, and if this nucleophile is used in excess in the absence of an added base, then the reaction may be carried out in an aqueous solvent, preferably a mixture of water and an organic solvent such as ethanol, 1,2-dimethoxyethane or dioxane, preferably ethanol. These reactions are carried out at room temperature or above, preferably at the reflux temperature of the solvent, for 16-48 hours. The product of Formula II is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula (52), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
An alternative method of preparation of compounds of formula (52), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2yl, 5,6-dihydro-4H-pyran-2yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen, is from intermediates of formula (57) as shown in Reaction Scheme XIV below. 
wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)0-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
Preparation of Compound of Formula (56)
N-Cyano-imido-S,S-dimethyl-carbonate, a compound of formula (55) which may be obtained commercially, for example from Fluka Chemie AG, is reacted with malonitrile in a polar solvent, preferably methanol or ethanol, in the presence of a base, preferably sodium methylate or sodium ethylate, at room temperature for 1-18 hours, preferably 14 hours. The product of formula (56), the sodium salt of 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide, is isolated by conventional means, and preferably purified by means of recrystallisation.
Preparation of Compound of Formula (57)
The compound of formula (56), the sodium salt of 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide, is reacted by addition to a large excess of anhydrous hydrogen chloride in an ethereal solvent, preferably diethyl ether, at 0xc2x0 C. and the mixture is allowed to warm slowly to room temperature for over 1-36 hours, preferably 18 hours. The product of formula (57), 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, is isolated by conventional means, and preferably purified by means of recrystallisation or chromatography. Alternatively, the compound of formula (56), the sodium salt of 2,2-dicyano-1-methylsulfanyl-vinyl-cyanamide, is reacted with hydrogen bromide in a protic solvent, preferably acetic acid, at 5xc2x0 C. and the mixture is allowed to warm slowly to room temperature for over 1-36 hours, preferably 1 hour. The product of formula (57), 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, is isolated by conventional means, and preferably purified by means of recrystallisation or chromatography.
Preparation of Compounds of Formula (52)
Boronic acid derivatives of formula (33), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, may be obtained commercially, or may be prepared by methods well known in the art. The compound of formula (57), 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile or 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, is reacted with a boronic acid derivative of formula (33) in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 2-8 hours, preferably about 4 hours. The product of formula (52) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula (52)
Trialkylstannane derivatives of formula (34), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R is methyl or n-butyl, may be obtained commercially, or may be prepared by methods well known in the art. The compound of formula (57), 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile or 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, is reacted with a trialkystannane derivative of formula (34) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine). The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 10-18 hours, preferably about 16 hours. The product of formula (52) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is pyrazol-1-yl (optionally substituted by lower alkyl or halogen). One method of preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is pyrazol-1-yl (optionally substituted by lower alkyl or halogen), is from intermediates of formula (84), the preparation of which is shown in Reaction Scheme XV below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R4 and R5 are hydrogen, and R12, R13 and R14 are independently hydrogen, lower alkyl, or halogen.
Preparation of Compounds of Formula (83)
The starting pyrazoles of formula (82) may be obtained commercially, or may be prepared according to methods well known in the art.
Compounds of formula (83) may be prepared by treating a compound of formula (57), either 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile or 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, with an excess of the pyrazole compounds of formula (82) in a polar non-protic solvent, such as N-methylpyrrolidone, N,N-dimethyl-formamide or diglyme, preferably N-methylpyrrolidone, in the presence of a base, such as sodium hydride, potassium hydride, or cesium carbonate, preferably cesium carbonate, at an elevated temperature, preferably 60-70xc2x0 C., for about 2-18 hours, preferably 16 hours. The product of formula (83) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (84)
The methylsulfanyl-pyrimidine compound of formula (83) is reacted with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an organic solvent, preferably dichloromethane, at room temperature. The product of formula (84), a methanesulfinyl-pyrimidine derivative, is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (84) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is pyrazol-1-yl (optionally substituted by lower alkyl or halogen). The methanesulfinyl-pyrimidine derivative of formula (84) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is pyrazol-1-yl (optionally substituted by lower alkyl or halogen), is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula II where A is oxygen or sulfur and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
An alternative method of converting a compound of formula (52) to a compound of Formula II, wherein A is oxygen or sulfur, and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is shown below in Reaction Scheme XVI. 
wherein A is oxygen or sulfur, R1 is as defined above, R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (58)
A compound of formula (52) is reacted with an excess of alkali metal hydroxide, preferably sodium hydroxide, in an aqueous solvent, preferably a mixture of water and an ethereal organic solvent such as 1,2-dimethoxyethane or dioxane, preferably dioxane. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., and preferably for about 16 h. The product of formula (58) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (58) may, however, be additionally purified by means of recrystallisation.
Preparation of compounds of Formula II where A is oxygen and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (58) is reacted with an excess of an appropriate organic halide of formula (8), such as a primary or secondary aliphatic halide, preferably an aliphatic bromide or a benzylic bromide, which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 2 hours. The product of Formula II, wherein A is oxygen and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (59)
A compound of formula (52) is reacted with an excess of alkali metal thiolate, preferably sodium thiolate, in a polar organic solvent, preferably ethanol. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., and preferably for about 16 h. The product of formula (59) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (59) may, however, be additionally purified by means of recrystallisation.
Preparation of compounds of Formula II where A is sulfur and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (59) is reacted with an excess of an appropriate organic halide of formula (8), such as a primary or secondary aliphatic halide, preferably an aliphatic bromide or a benzylic bromide, which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 2 hours. The product of Formula II where A is sulfur and R3 is lower alkyl, phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula (52), (58) and (59), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
An alternative method of preparation of compounds of formula (52), (58) and (59), in which R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen, is from intermediates of formula (61) as shown in Reaction Scheme XVII below. 
wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
The starting orthoester derivatives of formula (60) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art. 2-Cyanoacetamide (formula (62)) and 2-cyanothioacetamide (formula (44)) may both be obtained commercially.
Preparation of Compounds of Formula (61)
An orthoester derivative of formula (60) is reacted with cyanamide and acetic anhydride, preferably in the absence of solvent, at elevated temperature, preferably around 130-150xc2x0 C. for about 1 hour. The product of formula (61), an N-cyano-imidate ester derivative, is preferably purified by distillation.
Preparation of Compounds of Formula (58)
The N-cyano-imidate ester derivative of formula (61) is reacted with 2-cyanoacetamide of formula (62). The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 2 hours. The product of formula (58) is isolated by conventional means, and preferably purified by recrystallisation.
Preparation of Compounds of Formula (59)
The N-cyano-imidate ester derivative of formula (61) is reacted with 2-cyanothio-acetamide of formula (44). The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 3 hours. The product of formula (59) is isolated by conventional means, and preferably purified by recrystallisation.
Preparation of Compounds of Formula (52)
The compound of formula (59) is reacted with an excess of methyl iodide. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably room temperature, for 1-18 hours, preferably 2 hours. The product of formula (52) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula (58), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
An alternative method of preparation of compounds of formula (58), in which R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl, (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are both hydrogen, is from an intermediate of formula (86) as shown in Reaction Scheme XVIII below. 
wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
Preparation of compound of Formula (86)
The compound of formula (86), 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile, is known in the literature, and may be prepared in three steps from commercially available 2-amino-4,6-dihydroxy-pyrimdine (85) according to the procedure of Bell et al. (J. Heterocyclic Chem. 1983, 20, 41).
Preparation of Compounds of Formula (58)
Boronic acid derivatives of formula (33), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo [1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, may be obtained commercially, or may be prepared by methods well known in the art. The compound of formula (86), 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile, is reacted with a boronic acid derivative of formula (33) in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride, and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 2-8 hours, preferably about 4 hours. The product of formula (58) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula (58)
Trialkylstannane derivatives of formula (34), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofiuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R is methyl or n-butyl, may be obtained commercially, or may be prepared by methods well known in the art. The compound of formula (86), 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile, is reacted with a trialkystannane derivative of formula (34) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 10-18 hours, preferably about 16 hours. The product of formula (58) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, from chloro or triflate derivatives.
Another method of converting a compound of formula (58) to a compound of Formula II where A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is via intermediates of formula (63) or formula (64), the preparation of which is shown below in Reaction Scheme XIX. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula (63)
A compound of formula (58) is reacted with a chlorinating agent, preferably phosphorus oxychloride, preferably in the absence of solvent. The reaction is conducted at the reflux temperature for about 1-3 h, preferably about one and a half hours. The product of formula (63) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (63) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 18 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (64)
A compound of formula (58) is reacted with an alkanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and an excess of a non-nucleophilic base, preferably 2,6-di-tert-butylpyridine, in an organic solvent, preferably dichloromethane, at a temperature between 0xc2x0 C. and room temperature for about 16 hours. The product of formula (64) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (64) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 18 hours. The product of Formula II where A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, xe2x80x94(CH2)n-lower alkoxy, cyano, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, furxe2x80x94l (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4] dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, from the compound of Formula (86)
Another method of converting the compound of formula (86) to compounds of Formula II where A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3] dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is via intermediates of formula (88), the preparation of which is shown below in Reaction Scheme XX. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R4 and R5 are hydrogen.
Preparation of Compounds of Formula (87)
The compound of formula (86), 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile, is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of formula (87) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (88)
A compound of formula (87) is reacted with an alkanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and an excess of a non-nucleophilic base, preferably 2,6-di-tert-butylpyridine, in an organic solvent, preferably dichloromethane, at a temperature between 0xc2x0 C. and room temperature for about 16 hours. The product of formula (88) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
Boronic acid derivatives of formula (33), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of formula (88) is reacted with a boronic acid derivative of formula (33) in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably bis(triphenyl-phosphine)palladium(II) chloride, and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 2-8 hours, preferably about 4 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative preparation of compounds of Formula IL wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
Trialkylstannane derivatives of formula (34), wherein R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, and R is methyl or n-butyl, may be obtained commercially, or may be prepared by methods well known in the art. A compound of formula (88) is reacted with a trialkystannane derivative of formula (34) in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably bis(triphenyl-phosphine)palladium(II) chloride. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 10-18 hours, preferably about 16 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative preparation of compounds of Formula II, where A is xe2x95x90C less than , xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2CH2xe2x80x94.
One method of preparation of compounds of Formula II, wherein A is a carbon atom having olefinic or aromatic character and varying degrees of substitution, is from intermediates of formula (63) or (64), as shown in Reaction Scheme XXI below. 
wherein A is a carbon atom having olefinic or aromatic character and varying degrees of substitution, R1, R3, R6 and R7 are as defined above and R4 and R5 are hydrogen or lower alkyl.
Preparation of Compounds of Formula II Where A is xe2x95x90C less than 
A compound of formula (63), or a compound of formula (64), is reacted with an appropriate organometallic compound, which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a trimethyl-stannane derivative of formula (65); or a tributylstannane derivative of formula (66); of a boronic acid derivative of formula (67). In the case where an organostannane derivative of formula (65) or of formula (66) is used, the reaction is carried out in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine). The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 14-36 hours, preferably about 16 hours. The product of Formula II where A is xe2x95x90C less than  is isolated by conventional means, and preferably purified by chromatography or recrystallisation. In the case where a boronic acid derivative of formula (67) is used, the reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 14-36 hours, preferably about 16 hours. The product of Formula II where A is xe2x95x90C less than  is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula II Wherein A is xe2x80x94CHxe2x95x90CHxe2x80x94
A compound of formula (63), or a compound of formula (64), is reacted with an appropriate organometallic compound, which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: an olefin of formula (68); a trimethylstannane derivative of formula (69); or a tributylstannane derivative of formula (70); or a boronic acid derivative of formula (71). In the case where an olefin derivative of formula (68) is used, the reaction is carried in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), and an inorganic base, preferably cesium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 14-36 hours, preferably about 16 hours. The product of Formula II where A is xe2x80x94CHxe2x95x90CHxe2x80x94 is isolated by conventional means, and preferably purified by chromatography or recrystallisation. In the case where an organostannane derivative of formula (69) or of formula (70) is used, the reaction is carried out in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine). The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 14-36 hours, preferably about 16 hours. The product of Formula II where A is xe2x80x94CHxe2x95x90CHxe2x80x94 is isolated by conventional means, and preferably purified by chromatography or recrystallisation. In the case where boronic acid derivative of formula (71) is used, the reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 14-36 hours, preferably about 16 hours. The product of Formula II where A is xe2x80x94CHxe2x95x90CHxe2x80x94 is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula II, Wherein A is xe2x80x94Cxe2x89xa1Cxe2x80x94
A compound of formula (63), or a compound of formula (64), is reacted with an appropriate acetylinic compound of formula (72), which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably tetrahydrofuran), containing a palladium catalyst, preferably bis(triphenylphosphine) palladium(II) chloride, a base, preferably triethylamine, and a copper co-catalyst, preferably copper(I) iodide. The reaction is preferably carried out at a temperature between room temperature and the reflux temperature of the solvent, preferably about 50xc2x0 C., for about 1-18 hours, preferably about 3 hours. The product of Formula II where A is xe2x80x94Cxe2x89xa1Cxe2x80x94 is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Alternative Preparation of Compounds of Formula II Wherein A is xe2x80x94CH2CH2xe2x80x94
A compound of Formula II, wherein A is xe2x80x94CHxe2x95x90CHxe2x80x94, or a compound of Formula II, wherein A is xe2x80x94Cxe2x89xa1Cxe2x80x94, is reacted with hydrogen gas in an organic solvent (for example 1,2-dimethoxyethane, tetrahydrofuran, dioxane or ethanol, preferably a mixture of dioxane and ethanol) containing a hydrogenation catalyst, preferably 10% palladium on charcoal. The reaction is carried out at room temperature at a pressure of 1 atmosphere or above, preferably at one atmosphere, for about 2-36 hours, preferably about 16 hours. The product of Formula II where A is xe2x80x94CH2CH2xe2x80x94 is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein Axe2x80x94R1 is halogen, and R3 is xe2x80x94Oxe2x80x94 (CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl.
One method of preparation of compounds of Formula II, wherein Axe2x80x94R1 is halogen, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl, is from intermediates of formula (89), the preparation of which is shown in Reaction Scheme XXII below. 
wherein X is bromo or chloro, B is oxygen or sulfur, R4 and R5 are hydrogen, and R15 is xe2x80x94(CH2)nphenyl, or xe2x80x94(CH2)n-pyridyl, optionally substituted by lower alkyl.
Preparation of Compounds of Formula (89)
A compound of formula (57) is reacted with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an inert organic solvent, preferably a mixture of dichloromethane and N,N-dimethylformamide, at room temperature. The product of formula (89) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (89) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein Axe2x80x94R1 is halogen, and R3 is xe2x80x94Oxe2x80x94 (CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)nxe2x80x94pyridyl.
A compound of formula (89) is reacted with an appropriate nucleophilic compound of formula (90), which may be commercially available or may be prepared by methods well known in the art, in the presence of a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5). The reaction is carried out in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of Formula II, wherein Axe2x80x94R1 is halogen, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl.
One method of preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl, is from intermediates of formula (92), the preparation of which is shown in Reaction Scheme XXIII below. 
wherein X is bromo or chloro, A is nitrogen, oxygen or sulfur, B is oxygen or sulfur, R1 is as defined above, R4 and R5 are hydrogen, and R15 is xe2x80x94(CH2)nphenyl, or xe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl).
Preparation of Compounds of Formula (91)
A compound of formula (57) is reacted with an appropriate nucleophilic compound of formula (90), which may be commercially available or may be prepared by methods well known in the art, in the presence of a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5). The reaction is carried out in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 16 hours. The product of formula (91) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (92)
A compound of formula (91) is reacted with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an inert organic solvent, preferably dichloromethane, at room temperature. The product of formula (92) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (92) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl.
A compound of formula (92) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Conversion of Compounds of Formula II, wherein Axe2x80x94R1 is halogen, and R3 is xe2x80x94Oxe2x80x94 (CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl, to compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94 (CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl.
A method of converting compounds of Formula II, wherein Axe2x80x94R1 is halogen, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl, to compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94 (CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl, is shown in Reaction Scheme XXIV below. 
wherein X is bromo or chloro, A is nitrogen, oxygen or sulfur, B is oxygen or sulfur, R1 is as defined above, R4 and R5 are hydrogen, and R5 is. xe2x80x94(CH2)nphenyl, or xe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl).
Preparation of compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl.
A compound of Formula II, wherein Axe2x80x94R1 is halogen, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94 (CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl, is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at room temperature, for 1-18 hours, preferably 2 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is xe2x80x94Oxe2x80x94(CH2)nphenyl, xe2x80x94Oxe2x80x94(CH2)n-pyridyl (optionally substituted by lower alkyl), or Sxe2x80x94(CH2)n-pyridyl is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Conversion of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-methyl-furan-2-yl to compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromomethyl-furan-2-yl or 5-hydroxymethyl-furan-2-yl.
A method of converting compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-methyl-furan-2-yl to compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromomethyl-furan-2-yl or 5-hydroxymethyl-furan-2-yl is shown in Reaction Scheme XXV below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, and R4 and R5 are hydrogen.
Preparation of Compounds of Formula II, Wherein A is Nitrogen, Oxygen or Sulfur, and R3 is 5-bromomethyl-furan-2-yl
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-methyl-furan-2-yl, is reacted with a slight excess of N-bromosuccinimide in a non-polar organic solvent, preferably carbon tetrachloride, in the presence of a radical initiator, preferably benzoyl peroxide, and with concomitant irradiation from a high intensity light source, preferably a halogen lamp. The reaction is preferably carried out at room temperature for about 8-18 hours, preferably 8 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromomethyl-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-hydroxymethyl-furan-2-yl
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromomethyl-furan-2-yl, is reacted with an excess of silver nitrate in an aqueous solvent system, such as a mixture of water and a water-miscible polar organic solvent, preferably a mixture of water and acetone. The reaction is preferably carried out at room temperature, and preferably in the dark, for about 8-18 hours, preferably 16 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-hydroxymethyl-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Conversion of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is furan-2-yl to compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, 5-chloro-furan-2-yl, 5-methoxy-furan-2-yl, 5-methylsulfanyl-furan-2-yl, 5-ethoxycarbonyl-furan-2-yl, 5-(1-ethoxy-vinyl)-furan-2-yl, or 5-cyanomethyl-furan-2-yl.
Methods of converting compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is furan-2-yl to compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, 5-chloro-furan-2-yl, 5-methoxy-furan-2-yl, 5-methylsulfanyl-furan-2-yl, 5-ethoxycarbonyl-furan-2-yl, 5-(1-ethoxy-vinyl)-furan-2-yl, or 5-cyanomethyl-furan-2-yl are shown in Reaction Scheme XXVI below. 
wherein A is nitrogen, oxygen or Sulfur, R1 is as defined above, and R4 and R5 are hydrogen.
Preparation of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl.
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is furan-2-yl, is reacted with a slight excess of N-bromosuccinimide in a polar organic solvent, preferably N,N-dimethylformamide. The reaction is carried out at a temperature between room temperature and 50xc2x0 C., preferably 50xc2x0 C., for about 1-2 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-chloro-furan-2-yl.
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is furan-2-yl, is reacted with a slight excess of N-chlorosuccinimide in a polar organic solvent, preferably N,N-dimethylformamide. The reaction is carried out at a temperature between room temperature and 50xc2x0 C., preferably 50xc2x0 C., for about 1-2 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-chloro-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-methoxy-furan-2-yl.
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, is reacted with an excess of sodium methylate in a non-protic polar organic solvent, preferably 1,2-dimethoxyethane. The reaction is carried out at a temperature between room temperature and 50xc2x0 C., preferably 50xc2x0 C., for about 1-2 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-methoxy-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-methylsulfanyl-furan-2-yl.
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, is reacted with an excess of sodium methanethiolate in a non-protic polar organic solvent, preferably 1,2-dimethoxyethane. The reaction is carried out at a temperature between room temperature and 50xc2x0 C., preferably 50xc2x0 C., for about 1-2 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-methylsulfanyl-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula II wherein A is nitrogen, oxygen or sulfur, and R3 is 5-ethoxycarbonyl-furan-2-yl.
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, is reacted with carbon monoxide gas in a solvent mixture comprising ethanol and N,N-dimethylformamide. The reaction mixture also contains a palladium catalyst, preferably tris(dibenzylidineacetone)dipalladium chloroform complex, a catalytic amount of a monodentate ligand, preferably triphenylarsine, and an excess of an organic base, preferably triethylamine. The reaction is carried out at a pressure of 1-20 atmospheres, preferably 1 atmosphere, and at a temperature above room temperature, preferably about 90-100xc2x0 C., for about 8-18 hours, preferably about 16 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-ethoxycarbonyl-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-(1-ethoxy-vinyl)-furan-2-yl.
A compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, is reacted with a slight excess of (1-ethoxyvinyl)tributylstannane in an ethereal solvent (for example 1,2-dimethoxyethane, tetrahydrofuran or dioxane, preferably dioxane), containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 10-18 hours, preferably about 16 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-(1-ethoxy-vinyl)-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-cyanomethyl-furan-2-yl.
To prepare compounds of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-cyanomethyl-furan-2-yl, an excess of acetonitrile is reacted with a strong non-aqueous base, preferably potassium bis(trimethylsilyl)amide. The reaction is carried out in an ethereal solvent (for example, tetrahydrofuran, dioxane, diethyl ether, or 1,2-dimethoxyethane, preferably tetrahydrofuran), at a temperature of xe2x88x9278xc2x0 C. for about 1 hour, after which time a compound of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-bromo-furan-2-yl, is added, and the mixture allowed to warm gradually to xe2x88x9240xc2x0 C. over about 5-6 hours. The product of Formula II, wherein A is nitrogen, oxygen or sulfur, and R3 is 5-cyanomethyl-furan-2-yl, is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of compounds of Formula III, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy), thien-2.yl, fur-2.yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula III, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is from intermediates of formula (78), the preparation of which is shown in Reaction Scheme XXVII below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
Preparation of Compounds of Formula (74)
The starting nitrites of formula (73) may be obtained commercially, for example from Fluka Chemie AG, or may be prepared according to methods well known in the art.
To prepare compounds of formula (73), acetonitrile is reacted with about one equivalent of a strong non-aqueous base, for example a lower alkyl lithium, preferably n-butyl lithium. The reaction is carried out in an ethereal solvent (for example, tetrahydrofuran, dioxane, diethyl ether, or 1,2-dimethoxyethane, preferably tetrahydrofuran), at a temperature of xe2x88x9278 IC for about 15-30 minutes, preferably 15 minutes, after which time a slight excess of a nitrile of formula (73) is added, and the mixture allowed to warm gradually to 0xc2x0 C. over about 1-2 hours. The product of formula (74) is isolated by conventional means, and preferably used in the next step without further purification.
Preparation of Compounds of Formula (76)
A compound of formula (74) is reacted with a slight excess of 2-cyanoacetic acid of formula (75) and a slight excess of acetic anhydride in an ethereal solvent (for example dioxane or tetrahydrofuran, preferably dioxane). The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 1-2 hours, preferably about 90 minutes. The product of formula (76) is isolated by conventional means, and preferably purified by recrystallisation.
Preparation of Compounds of Formula (77)
A compound of formula (76) is reacted in an alcoholic solvent, preferably ethanol, with a base, preferably sodium ethylate. The reaction is preferably performed at the reflux temperature of the solvent, preferably about 100xc2x0 C., for 1-2 hours, preferably 1 hour. The product of formula (77) is isolated by conventional means, and preferably purified by recrystallisation.
Preparation of Compounds of Formula (78)
A compound of formula (77) is reacted with an alkanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and an excess of a non-nucleophilic base, preferably 2,6-di-tert-butylpyridine, in an organic solvent, preferably dichloromethane, at a temperature between 0xc2x0 C. and room temperature for about 16 hours. The product of formula (78) is isolated by conventional means, and is preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula III wherine A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (78) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-72 hours, preferably 48 hours. The product of Formula III where A is nitrogen, oxygen or sulfur and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy), thien-2yl, fur-2yl (optionally substituted by lower alkyl, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, xe2x80x94C(xe2x95x90CH2)O-lower alkyl, 4,5-dihydrofuran-2-yl, 5,6-dihydro-4H-pyran-2-yl oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula IV, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
One method of preparation of compounds of Formula IV, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is from intermediates of formula (81), the preparation of which is shown in Reaction Scheme XXVIII below. 
wherein A is nitrogen, oxygen or sulfur, R1 is as defined above, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-yl-isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
Preparation of Compounds of Formula (79)
A compound of formula (74), is reacted with an excess of 2-cyanothioacetamide of formula (44) in an ethereal solvent (for example dioxane or tetrahydrofuran, preferably dioxane). The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 12-72 hours, preferably about 60 hours. The product of formula (79) is isolated by conventional means, and preferably purified by chromatography or recrystallisation.
Preparation of Compounds of Formula (80)
A compound of formula (79) is reacted with about one equivalent of methyl iodide. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of about one equivalent of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably room temperature, for 30-90 minutes, preferably about 30 minutes. The product of formula (80) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Preparation of Compounds of Formula (81)
The compound of formula (80) may be converted to a compound of formula (81) by reacting a compound of formula (80) with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an organic solvent, preferably dichloromethane, at room temperature. The product of formula (81) is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (81) may, however, be additionally purified by means of chromatography or recrystallisation.
Preparation of compounds of Formula IV, wherein A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
The compound of formula (81) is reacted with an appropriate nucleophilic compound of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); a primary or secondary aliphatic thiol or an aromatic thiol, in each case used together with a non-nucleophilic base, preferably 1,8-diazabicyclo [5.4.0]undec-7-ene (1,5-5) (DBU); a primary or secondary aliphatic amine which is preferably used in excess in the absence of an added base; the inorganic salt of a primary or secondary aliphatic amine, such as a hydrochloride salt, which is used together with a non-nucleophilic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); an alkali metal alcoholate of a primary or secondary aliphatic alcohol or of an aromatic alcohol, preferably a sodium or potassium alcoholate, which is preferably used in excess; or an alkali metal thiolate of a primary or secondary aliphatic thiol or of an aromatic thiol, preferably a sodium or potassium thiolate, which is preferably used in excess. These reactions may be carried out in a non-protic polar solvent such as acetonitrile or in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-48 hours, preferably 16 hours. The product of Formula IV where A is nitrogen, oxygen or sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Alternative preparation of compounds of Formula IV, wherein A is sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl.
An alternative method of converting a compound of formula (79) to a compound of Formula IV, wherein A is sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo[1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is by reaction of a compound of formula (79) with an excess of an appropriate organic halide of formula (8), such as a primary or secondary aliphatic halide, preferably an aliphatic bromide or a benzylic bromide, which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in a polar solvent, preferably methanol or ethanol, in the presence of an excess of a base, preferably sodium methylate or sodium ethylate, at room temperature or above, preferably at the reflux temperature of the solvent, for 1-18 hours, preferably 1 hour. The product of Formula IV where A is sulfur, and R3 is phenyl (optionally substituted by lower alkyl, lower alkoxy, or halogen), thien-2-yl, fur-2-yl (optionally substituted by lower alkyl, halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)n-lower alkoxy, CHF2, or CH2F), 2,3-dihydro-benzo[1.4]dioxin-6-yl, benzo [1.3]dioxol-5-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl, oxazol-2-yl, benzofuranyl, or pyrazin-2-yl, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Conversion of Compounds of Formula I to Other Compounds of Formula I
The compounds of Formula I wherein X, Y, A, R1, R2 and R3 are as defined above and R4 and R5 are hydrogen may be converted to other compounds of Formula I by replacing one or both hydrogens of R4 and R5 with other groups:
For example, a compound of Formula I where R4 and R5 are hydrogen is reacted with an acylating agent, for example an acyl chloride or an acyl anhydride, optionally in the presence of a catalyst such as 4-dimethylaminopyridine. The reaction is carried out in an organic solvent such as dichloromethane containing a base such as pyridine. The reaction is performed at a temperature between 0xc2x0 C. and 100xc2x0 C., preferably at room temperature, for about 1 to 18 hours. The resulting monoacyl product, a compound of Formula I where R4 is acyl and R5 is hydrogen, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Isolation and Purification of the Compounds
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the Preparations and Examples herein below. However, other equivalent separation or isolation procedues could, of course, also be used.
Salts of Compounds of Formula I
The compounds of Formula I may be basic, for example in cases where the residue R1 contains a basic group such as an aliphatic or aromatic amine moiety, or in cases where X is N and Y is CH, or in cases where X is CH and Y is N. In such cases the compounds of Formula I may be converted to a corresponding acid addition salt.
The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0xc2x0 C. and 50xc2x0 C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The acid addition salts of the basic compounds of Formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are adenosine receptor ligands.
The compounds were investigated in accordance with the tests given hereinafter.
The gene encoding human adenosine A1 receptor was recombinantly introduced and expressed in chinese hamster ovary (CHO) cells using the semliki forest virus expression system. Cells were harvested, washed twice by centrifugation, homogenised and again washed by centrifugation. The final washed membrane pellet was suspended in a Tris (50 mM) buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 10 mM MgCl2 (pH 7.4) (buffer A). The [3H]-DPCPX (([propyl-3H]8-cyclopentyl-1,3-dipropyxanthine); 0.6 nM) binding assay was carried out in 96-well plates in the presence of 2.5 xcexcg of membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA beads and 0. I U adenosine deaminase in a final volume of 200 xcexcl of buffer A. Non-specific binding was defined using xanthine amine congener (XAC; 2 xcexcM). Compounds were tested at 10 concentrations from 10 xcexcM-0.3 nM. All assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for 1 hour at room temperature before centrifugation and then bound ligand determined using a Packard Topcount scintillation counter. IC50 values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation.
The gene encoding human adenosine A2A receptor was recombinantly introduced and expressed in chinese hamster ovary (CHO) cells using the semliki forest virus expression system. Cells were harvested, washed twice by centrifugation, homogenised and again washed by centrifugation. The final washed membrane pellet was suspended in a Tris (50 mM) buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 10 mM MgCl2 (pH 7.4) (buffer A). The [3H]-SCH-58261 (Dionisotti et al., 1997, Br. J. Pharmacol. 121, 353; 1 nM) binding assay was carried out in 96-well plates in the presence of 2.5 xcexcg of membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA beads and 0.1 U adenosine deaminase in a final volume of 200 xcexcl of buffer A. Non-specific binding was defined using xanthine amine congener (XAC; 2 EM). Compounds were tested at 10 concentrations from 10 xcexcM-0.3 nM. All assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for 1 hour at room temperature before centrifugation and then bound ligand determined using a Packard Topcount scintillation counter. IC50 values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation.
The gene encoding human adenosine A3 receptor was recombinantly introduced and expressed in chinese hamster ovary (CHO) cells using the semliki forest virus expression system. Cells were harvested, washed twice by centrifugation, homogenised and again washed by centrifugation. The final washed membrane pellet was suspended in a Tris (50 mM) buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 10 mM MgCl2 (pH 7.4) (buffer A). The [125I]-AB-MECA ([N(6)-(4-amino-3-iodobenzyl)-5xe2x80x2-N-methylcarbamoyl-adenosine]; 0.05 nM) binding assay was carried out in 96-well plates in the presence of 20 xcexcg of membrane protein and 0.1 U adenosine deaminase in a final volume of 200 xcexcl of buffer A. Non-specific binding was defined using xanthine amine congener (XAC; 2 xcexcM). Compounds were tested at 10 concentrations from 10 xcexcM-0.3 nM. All assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for 1 hour at room temperature before filtration through Whatman Unifilter GF/C 96-well filter plates (preincubated with 0.3% polyethyleneimine). Filters were washed 3 times with 0.3 ml of cold (4xc2x0 C.) Tris (50 mM)-Nacl (120 mM) buffer (pH 7.4). Microscint 40 scintillation fluid (50 xcexcl) was added to each well and the wells sealed. After gentle shaking for 20 min, plates were counted on a Packard Topcount scintillation counter. IC50 values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation.
In the following table the affinity to the human A2a receptor is shown for the preferred compounds, given as pKi.
Furthermore, it has been shown that compounds of formula I have a high selectivity toward the A1 and A3 receptor, as it is shown in the table below:
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of supositories, parenterally, e.g. in the form of injection solutions.
The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
In accordance with the invention compounds of formula I as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the adenosine receptor antagonistic activity, such as Alzheimer""s disease, Parkinson""s disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents and for the production of corresponding medicaments.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson""s disease.
The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
Manufacturing Procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50xc2x0 C.
3. Pass the granules through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press.
Manufacturing Procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.